Bloom's Syndrome
Introduction Bloom's syndrome (BS) was characterized by Dr. David Bloom in 1954 1. In patients with BS there is a mutation in the gene encoding Bloom (BLM). BLM is a RecQ DNA helicase. DNA helicases unwind the double helix of the DNA creating single stranded DNA for DNA polymerases. DNA polymerases use the single stranded DNA at as a template for the new strand. BLM has been shown to be involved in DNA replication, recombination and repair; helping to minimize crossovers, thus leading to genome stability 1,2,3. There is an elevated risk of BS in certain Jewish populations, particularly the Ashenazi. BS is a rare, autosomal recessive disorder, therefore both copies of the gene need to be mutated to have the disease 1,2,3. Gruber et al. looked into the risk of cancer in heterozygotes and found that there is an increased risk of colorectal cancer in carriers of BS. They hypothesized that this could be observed because maybe only having half fully functional BLM is insufficient or perhaps the colonic stem cell lost the other functioning allele 2. Cleary et al. looked into heterozygosity and found that there was not a significant increased risk of cancer in BLM carriers. They also mentioned that the mouse models used to support the previously reported data may not be a good model because of the differences. The BLM mutation is embryonically lethal in mice 3. Phenotype BS patients tend to have proportional dwarfism, sun-sensitivity, skin pigmentation, increased risk of infections and diabetes, male sterility, and a much higher risk of cancer. The dwarfism is not yet understood but many of the other phenotypes can be explained by the significant amount of chromosomal damage, in the form of rearrangements, gaps, and breaks 1,2,3. Patients are diagnosed with BS because their cells exhibit a 10-fold higher rate of sister chromosome exchanges most likely from improper resolution of Holliday junctions in homologous recombination1,3. BLM is part of the disolvasome which resolves Holliday junctions during homologous recombination. A mutation in BLM has impacts on repairing DNA, homologous recombination of double strand breaks, DNA-replication checkpoint during anaphase. These results taken together account for the massive chromosome recombinations and DNA mutations seen in BS patients 1. Genotype BLM is located on the 15th chromosome. 23 and me tests 33 known single nucleotide polymorphisms (SNPs) associated with the BLM gene; although currently there are more than 60 BLM mutations believed to cause BS. The SNP in the BLMAsh gene I looked at is ATCTGA to TAGATTC (a frame shift mutation delATC TGA insTAG ATT C 2,3), both of Dr. Burke's genes are the ATCTGA. This frame shift was discovered by Roa et al. 3. Lesson You should learn that you are not a carrier for BLM syndrome, at least for BLMAsh . I was surprised to see BS on the 23 and Me website because it seems like you would know if you have BS. It could be important if you had a strong Jewish heritage to know if you were a carrier. References 1Manthei, K.A., and Keck, J.L. 2013. Cell Mol Life Sci. 70;4067-84. PMID: 23543275 2Gruber, S.B. et al. 2002 Science 297. PMID:12242432 3 Cleary, S.P. et al. 2003. Cancer Res. 63:1769-71. PMID:12702560 4 Roa, B.B., Savino, C.V., and Richards, C.S. 1999. Genet Test. 3:219:21 PMID:10464671